Non-steroidal anti-inflammatory drugs (NSAIDs) including aspirin have been used successfully in large numbers of patients with arthritis (including rheumatoid and osteoarthritis), and dysmenorrhea to relieve mild to moderate pain. It is well recognized that NSAIDs have a high incidence of gastrointestinal (GI) side effects. Serious GI adverse events such as bleeding, ulceration, and perforation can occur at any time in patients treated with regular doses of aspirin or other NSAIDs. The incidence of such adverse events ranges from 1-4% for studies without routine endoscopic surveillance to about 16% in studies where patients undergo regular endoscopic assessments.
The adverse GI effects of NSAIDs are a major concern in the use of these otherwise effective therapies. To date the efforts to produce a NSAID without these GI side effects have produced only marginal improvements. Misoprostol, a prostaglandin analogue, has been approved as a therapy to prevent NSAID-induced mucosal injury. Unfortunately, this compound has its own limitations to use. Consequently, mucosal protection remains an issue with aspirin and other NSAIDs.
Conventional formulations for reducing gastric distress usually involve either using pH buffering agents, coating the drug particles with various substances that are resistant to digestion and embedding them in a tablet matrix, or capsule formulation that is resistant to disintegration in the stomach. These latter formulations usually delay the release of the drug until it gets past the stomach and further down in the jejunum where it is then released. However, no approach so far has provided a readily acceptable rapid release composition that moderates the ulcerogenic action of NSAID in some portions of the population. It is therefore desirable to find a formulation of an NSAID that would provide rapid onset of action and a mucosal protective effect for the subject to whom it is administered, that is, it would reduce the gastric distress and/or ulcerogenic effect of an NSAID when delivered to a subject in need thereof.
Polysaccharide gums of hydrocolloids are a diverse class of substances that are hydrophilic and swell when in contact with water. When hydrated, they exhibit various degrees of viscosity. Polysaccharide hydrocolloids may contain galactose, galacturonic acid residues, mannose and sometimes xylose and arabinose. Structurally, they are similar to hemicellulose and when dissolved in water produce mucilage or gel. Some common polysaccharides used in the food and pharmaceutical industry are pectin, galactomannan gums, such as guar gum and locust bean gum, algal polysaccharides, such as agar and carrageenan, modified celluloses such as the cellulose ethers and esters and bacterial gums such as xanthan. The viscosity of these various substances will vary depending upon their molecular weight and structure.
Harju and Sajanti reported that oral administration of large quantities of guar gum provided protection against stress-induced ulceration in the rat (In vivo 5:397-400, 1991). In addition, Rafatullah et al. reported that an ethanol extract of guar (not guar itself) provided protection against several models of mucosal injury in the rat, including ethanol, stress, sodium chloride, indomethacin, and sodium hydroxide (Int. Jugaslov. Pharmacy 32:163-170, 1994).
A significant problem associated with high-viscosity water-soluble polymers is their ability to hydrate. Hydration is particularly difficult when these polymers are compressed into solid dosage forms. Most of the polymers used as excipients in pharmaceutical dosage forms are used at fairly low levels (e.g., 2 to 5 weight %) and principally as fillers or diluents. Of all the water-soluble polymers, guar gum probably possesses the highest molecular weight and exhibits the greatest viscosity when hydrated. Guar gum has been used at such low levels in a variety of products such as Quinidex.RTM. brand quinidine sulfate, Sine-Off.RTM. brand aspirin and acetaminophen, Bayer.RTM. brand aspirin, and Premarin.RTM. brand estrogen tablets. No mucosal protective effect has been reported at such low doses. The molecular weight of guar gum is reported as in the range of 1-2.times.10.sup.6 daltons (J. Chromatogr. 1981; 206, 410 and Carbohyd. Polymers, 1984; 4,299). Other hydrocolloids which come within the above limitations include solid dosage forms that contain about 5% by weight of high-viscosity gel-forming polysaccharides and are subject to surface gelation and the inability to fully hydrate the dosage form. Tablets containing elevated levels of high-viscosity polysaccharides begin to gel and hydrate, but the hydration stops at a certain point. The core of the tablet remains dry and therefore not all the drug may be released. The dissolution tests of such tablets demonstrate that only 40% to 70% of the drug is actually released after eight hours and, in many cases, even after 24 hours a significant amount of the drug is not released. At the other end of the spectrum, tablets containing high amounts of high-viscosity polysaccharides, when formulated differently, can result in dose dumping or the immediate release of the drug, and therefore cannot be used for sustained release formulations, because they immediately disintegrate upon reaching the stomach or in a dissolution vessel.
Thus, there is substantial interest in developing novel oral formulations (particularly tablets or capsules) which allow for the release of an NSAID for rapid onset of action while providing a mucosal protective effect on the gastrointestinal tract, i.e., the ulcerogenic effect of the NSAID is reduced.